Hypothesis: Tim-3/Galectin-9, A New Pathway for Leukemia Stem Cells Survival by Promoting Expansion of Myeloid-Derived Suppressor Cells and Differentiating into Tumor-Associated Macrophages

Despite the improvements in chemotherapy, about 60 % of acute myeloid leukemia (AML) remission patients still relapse. Leukemic stem cells (LSCs) are the main causes for the relapse and refractory. T cell immunoglobulin mucin-3 (TIM-3), a specific surface molecule expressed on LSCs in most types of AML, is a candidate for AML LSC-targeted therapies. It is important to know how this molecule functions in the maintenance of LSCs and suppression of anti-tumor immunity. Recent data have shown that Tim-3 which expresses on T cells can suppress immune responses indirectly by inducing expansion of myeloid-derived suppressor cells (MDSCs). MDSCs at the leukemia site can also differentiate into tumor-associated macrophages (TAMs). TAMs can promote proliferation and survival of LSCs by the diversion of adaptive immunity and the facilitation of extracellular matrix remodeling, angiogenesis, and lymphangiogenesis. Our previous study in AML patient bone marrow samples showed CD68(+) macrophages around AML clone. Based on the known evidence and our experimental findings, we hypothesize that Tim-3, which specifically expresses on LSCs, is beneficial for LSCs survival and AML progression by promoting expansion of MDSCs and differentiating into TAMs at the leukemia site.